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It is becoming increasingly clear that PD-1/ PD-L1 and CTLA-4 represent just the tip of the iceberg when it comes to manipulating the immune system to fight cancer, and the number of known checkpointsâ€”and with it the list of potential drug targetsâ€”has expanded in recent years.
Since the approval of ipilimumab (Yervoy) for the treatment of patients with metastatic melanoma in 2011, the targeting of immune checkpoints— signaling pathways that regulate the activity of T cells—has gone from strength to strength.
Impressive, durable responses have been observed in a variety of tumor types for which conventional therapies historically have had limited success. Thanks to an improved toxicity profile, agents that target programmed cell death-1 (PD-1) and its ligand, PD-L1, have been garnering most of the attention in the field, shifting the focus away from the cytotoxic T-lymphocyte antigen-4 (CTLA-4) checkpoint at which ipilimumab is aimed.
Yet it is becoming increasingly clear that PD-1/ PD-L1 and CTLA-4 represent just the tip of the iceberg when it comes to manipulating the immune system to fight cancer, and the number of known checkpoints—and with it the list of potential drug targets—has expanded in recent years. These include targeting inhibitory receptors, which release the brakes on the antitumor immune system, and costimulatory receptors, which hit the accelerator. Biotech startups and university spinoffs are competing with larger companies already heavily invested in the immune checkpoint market to develop drugs against these new targets, fueling the clinical development of agents with diverse mechanisms of action.
The immune system signaling networks that regulate T-cell functions offer many potential targets.
Hebeisen M, Oberle SG, Presotto D, et al. Molecular insights for optimizing T cell receptor specificity against cancer. Front Immunol. 2013;19;4:154. doi: 10.3389/fimmu.2013.00154. eCollection 2013.
Although progress in the field has been undeniable, many researchers feel the next significant advancements are most likely to come from combination therapy. Indeed, 2015 witnessed the first FDA approval of a combination regime of immune checkpoint inhibitors (nivolumab and ipilimumab) and this is quickly becoming a central focus of ongoing research with emerging and established drugs.It is well understood that cancer cells evolve the ability to overcome the immune response mounted against them by hijacking immune checkpoint pathways. The term immune checkpoint generally refers to a range of receptors expressed on the surface of immune cells that regulate their activity. In normal cells, checkpoint pathways play an important role in activating the cytotoxic T cells of the immune system. T cells are activated when they encounter antigen-presenting cells (APCs) bearing foreign antigens, which engage the T-cell receptor (TCR). This is coupled with a second signal that determines whether the T cell is turned on (a costimulatory signal) or off (a coinhibitory signal) in response to a particular antigen. This second step is vital in ensuring that the immune system does its job effectively, without attacking normal cells.
Cancer cells subvert this process by altering the expression of various components of the immune checkpoint pathways to achieve their end goal—suppressing the activation of T cells. This essentially provides them with a means of “masking” themselves from the antitumor immune response. Thus, the immune-oncology field embraced the development of drugs targeting the immune checkpoints in hopes that these would allow tumor-infiltrating T cells to once again seek out and destroy tumor cells.Both PD-1 and CTLA-4 are inhibitory immune checkpoints, meaning that their normal role in the cell is to switch off the T cell. Thus far, the drugs that are currently approved or in development are antagonists that seek to block the activity of PD-1 and CTLA-4, which are highly expressed on the surface of tumor cells.
In the anti-PD-1 category, the FDA has approved nivolumab (Opdivo), which has indications in melanoma, non—small cell lung cancer (NSCLC), and renal cell carcinoma; and pembrolizumab (Keytruda), which also has been approved in melanoma and NSCLC. As of now, ipilimumab remains the only CTLA-4–targeting drug to gain approval, but more inhibitors of this checkpoint are in development.
Meanwhile, basic scientific research has uncovered more detail about the complexities of immune checkpoint signaling, and numerous new inhibitory and stimulatory targets are being explored.Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors and a homolog of CD4, which is expressed on a number of different types of immune cells, including T cells. It negatively regulates T-cell proliferation and activation in a manner similar to that of CTLA-4 and PD-1. It is also thought to play a role in the suppressive functions of T-regulatory cells and in the maturation and activation of dendritic cells.
Three drugs targeting LAG-3 are currently in clinical development. IMP321 is a soluble LAG-3 immunoglobulin fusion protein that activates dendritic cells. A phase II trial in combination with paclitaxel in patients with hormone receptor— positive metastatic breast cancer is ongoing (NCT02614833). Prima BioMed, which is developing the drug, also recently reported that the company intends to begin a phase I clinical trial of IMP321 in combination with an approved checkpoint inhibitor in patients with metastatic melanoma in Australia in early 2016, the socalled TACTI-mel trial.
AML indicates acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CRPC, castration-resistant prostate cancer; CTCL, cutaneous T-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; GITR, glucocorticoid-induced TNFR family related gene; HNSCC, head and neck squamous cell carcinoma; IDO, indoleamine 2,3-dioxygenase; KIR, killer cell immunoglobulin-like receptor; LAG-3, lymphocyte activation gene 3; MDS, myelodysplastic syndrome; NKG2A, NK cell inhibitory receptor; NSCLC, non—small cell lung cancer; OX40, tumor necrosis factor receptor superfamily, member 4; RCC, renal cell carcinoma; SCC, squamous cell carcinoma; TGFRβ, transforming growth factor receptor beta; TIM-3, T-cell immunoglobulin and mucin domain 3.
The two other drugs targeting LAG-3 are monoclonal antibodies. Bristol-Myers Squibb and Novartis are developing BMS-986016 and LAG525, respectively. The former is being evaluated as monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and multiple myeloma (NCT02061761), and as monotherapy and in combination with nivolumab in patients with solid tumors (NCT01968109). A single phase I/II trial of LAG525 is ongoing, as monotherapy and in combination with PDR001 (a novel anti-PD-1 antibody) in patients with advanced malignancies (NCT02460224).B7-H3 is one of the most recently identified members of the B7 superfamily of membrane proteins found on APCs, to which the ligands of PD-1 and CTLA-4 also belong.
MacroGenics, a biopharmaceutical company specializing in immunotherapeutics, is developing enoblituzumab (MGA271), a B7-H3-targeting monoclonal antibody that has been engineered with a modified fragment crystallizable (Fc) region that enhances binding to the activating Fcγ receptor CD16, which potentiates antibody-dependent cellular cytotoxicity (ADCC). This drug is undergoing phase I clinical trials as monotherapy (NCT01391143) and in combination with pembrolizumab (NCT02475213) or ipilimumab (NCT02381314) in patients with refractory cancers.
Interim results from the monotherapy trial were reported at the 2015 Society for Immunotherapy of Cancer (SITC) Annual Meeting in National Harbor, Maryland. The dose-escalation portion of the study has been completed and a 2-component cohort expansion is ongoing.
Enoblituzumab was well-tolerated in patients with a range of B7-H3—positive tumors, including melanoma and prostate cancer.
There were no dose-limiting toxicities (DLTs) and no maximum tolerated dose (MTD) was identified up to 15 mg/kg. Common treatment-related adverse events (TAEs) included fatigue, infusion- related reaction, nausea, chills, and vomiting. Patients experienced disease stabilization ≥12 weeks and tumor shrinkage between 2% and 69% across the different tumor types.Although the primary focus thus far has been on immune checkpoints that regulate T-cell activity, checkpoint pathways also play an important role on other types of immune cells. Among the new wave of immune checkpoint inhibitors are those targeting proteins found on NK cells, known as killer cell inhibitory receptors.
These receptors, which transduce inhibitory signals into the NK cell upon ligand binding, can be grouped into two sub-classes; killer cell immunoglobulin-like receptors (KIRs) and C-type lectin transmembrane receptors (which include the NKG family).
Innate Pharma is taking the first steps in the clinical exploration of NK cell-targeting. The company developed lirilumab in collaboration with Bristol-Myers Squibb, which is undergoing phase II clinical trials in combination with 5-azacytidine in patients with relapsed/refractory acute myeloid leukemia (AML) (NCT02399917); in combination with nivolumab plus 5-azacytidine in myelodysplastic syndromes (MDS) (NCT02599649); and in combination with rituximab in patients with relapsed/refractory or high-risk untreated CLL (NCT02481297).
Innate Pharma is also developing the anti-KIR antibody IPH4102 and the anti-NKG2A antibody IPH2201, in phase I/II and phase 1Iclinical trials, respectively. In 2014, the results of a phase II trial of single-agent IPH2101 in smoldering multiple myeloma proved disappointing. The trial was terminated due to a lack of patients meeting the primary objective, but researchers suggested that combination therapy may yield clinically significant responses. More recently, the results of a phase I trial of IPH2101 in combination with lenalidomide in patients with myeloma were reported. Among 15 patients there were 5 objective responses and the biologic endpoint of full KIR occupancy was achieved at all doses of IPH2101 (0.2 mg/kg, 1 mg/kg, or 2 mg/kg). There were 5 serious AEs, but no autoimmunity was observed.The immune checkpoint field has also been expanded to include molecules that are involved in other forms of T-cell inhibition. A central focus has been on the enzyme indoleamine-2,3 dioxygenase (IDO), which acts in the metabolic pathway that breaks down the essential amino acid tryptophan. IDO exerts an immunosuppressive effect in several different ways: it depletes local tryptophan levels and creates bioactive tryptophan metabolites, both of which are toxic to effector T cells, inducing cell death; and it has also been shown to activate regulatory T cells, which suppress effector T cells. IDO expression has been observed in a wealth of tumor types and often correlates with poor survival, suggesting that tumors may use IDO to subdue the antitumor immune response.
The development of IDO inhibitors is being pioneered by NewLink Genetics. Indoximod (1-methyl tryptophan), which is a tryptophan mimetic, was the first to enter clinical testing and continues to be evaluated in a number of clinical trials. In collaboration with Genentech, NewLink has also developed GDC-0919, a small molecule inhibitor of IDO, which is currently in phase I trials in patients with solid tumors.
Preliminary safety data from a phase II trial evaluating indoximod in combination with docetaxel were recently presented at the 2015 San Antonio Breast Cancer Symposium. The regimen was well tolerated in 128 evaluable patients with HER2-negative metastatic breast cancer who had not received prior chemotherapy in that setting. Efficacy findings were not disclosed.
At the 2015 European Cancer Congress, early data were presented for a study into GDC-0919 in patients with recurrent or advanced solid tumors. Among 17 patients available for tumor assessment, stable disease was achieved in 37%. The drug had an acceptable safety profile; the most common TAEs were pruritus, fatigue, and decreased appetite. The MTD was not reached and the drug was well-tolerated up to a dose of 800 mg twice-daily on a 21/28 day cycle.
Incyte Corporation is also developing a small molecule IDO inhibitor, epacadostat (INCB024360). Numerous clinical trials are ongoing and early data from a phase I/II trial of epacadostat in combination with pembrolizumab in patients with advanced cancers were presented at SITC.
Responses were observed in all tumor types among the 19 patients who were evaluable for efficacy. Among 7 patients with melanoma, the ORR was 57%, including 2 complete responses (CR), and the disease control rate (DCR) was 86%. Among those with renal cell carcinoma, the ORR was 40% and DCR 80%. Grade ≥3 immune-related mucosal inflammation and rash.Historically, the other side of the equation—the “On” switch—has been largely ignored in terms of cancer drug development. More recently, it has come to light that many of the costimulatory immune checkpoints are also dysregulated in cancer cells. Thus, targeting these molecules with agonists that serve to promote their activity has emerged as a promising new anticancer strategy. The majority of costimulatory molecules studied in this context belong to the tumor necrosis factor receptor (TNFR) superfamily, a group of cytokine receptors that share the ability to bind tumor necrosis factor (TNF). Among them are CD40, OX40, CD27, glucocorticoid-induced TNFR-related protein (GITR), and 4-1BB (also known as CD137).OX40, also known as CD134, is a TNF receptor primarily found on the surface of activated cytotoxic and regulatory T cells. Having licensed the OX40 agonist platform from AgonOx, a spin-off from the Providence Cancer Center in 2011, MedImmune, LLC is developing three different OX40-targeting agonists: MEDI6383, MEDI0562, and MEDI6469.
A phase I clinical trial of the latter was completed in 2013 and clinically validated OX40 as a potent immune checkpoint target; 12 out of 30 patients had regression of at least 1 metastatic lesion with only 1 treatment cycle. The monoclonal antibody is currently under study in colorectal, prostate, breast, and head and neck cancers.CD40 is found on APCs and is required for their activation. Several CD40 agonists are in early-stage development. Although no trials are currently ongoing, researchers from the University of Pennsylvania presented the results of an open-label phase I trial into CP-870,893 at the 2015 American Association for Cancer Research Annual Meeting. The combination of CP-870,893 with the CTLA-4— targeting antibody tremelimumab in patients with metastatic melanoma demonstrated a 27.3% ORR among 22 evaluable patients, including 2 CRs and 4 partial responses. The most common TAE was grade 1-2 cytokine release syndrome, and DLTs included colitis, hypophysitis, and uveitis.Glucocorticoid-induced tumor necrosis factor receptor (GITR) is expressed on CD4- and CD8-positive T cells, in addition to T-regulatory cells, NK cells, and dendritic cells. It binds to its ligand on APCs and endothelial cells to promote T-cell activation. A number of GITR agonists are in phase I clinical trials, including TRX518, the sole drug being developed by biotech startup GITR Inc. It is being tested in patients with stage III/IV melanoma or other solid tumors (NCT01239134). Other GITR agonists include MK-4166 (Merck) and MEDI1873 (MedImmune), both in phase I clinical trials in patients with advanced solid tumors (NCT02132754 and NCT02583165, respectively). MK-4166 is being examined as monotherapy and in combination with pembrolizumab.
Jane de Lartigue, PhD, is a freelance medical writer and editor based in New Haven, Connecticut